The goal of this project is for the NSRRC and the MMRRC at the University of Missouri (MU) to work with the Duke University (Duke) CTSA to utilize existing mouse and pig animal models for discovery of drugs to treat Urinary tract infection (UTI). Urinary tract infections (UTIs) are the second most common type of infection in humans, costing $1.6 billion per year (US) and $90 million in antibiotics alone. Rising antibiotic resistance and the emergence of difficult-to-treat bacteria have complicated contemporary therapy, particularly limiting oral treatment options. We have discovered that uropathogenic Escherichia coli (UPEC), the leading cause of UTIs, invades into the bladder epithelium in cAMP-regulated fusiform vesicles to cause bladder infections (cystitis). Treatment of experimental cystitis with cAMP-elevating drugs results in expulsion of internalized bacteria and attenuation of infection. We hypothesize that cAMP modulation therapy will be widely effective against UPEC and non-UPEC uropathogens, including muti-drug resistant organisms. cAMP modulation therapy may also be employed as an antibioticsparing therapy in UTI associated with neurogenic bladder. We will use comparative experimental models of cystitis in mice and pigs to identify highly efficacious cAMP modulators in the treatment of cystitis. Experimental UTI will also be studied in 5-hydroxytryptamine 3a knockin mice that have a neurogenic bladder phenotype, demonstrating an antibiotic-sparing therapy for this recurrent UTI-associated disease. Together, these studies will demonstrate the cross-mammalian species effects of cAMP modulation therapy on UTI, elucidate its novel role as therapy for difficult to treat infections, and yield specific agents for future human clinical trials. PUBLIC HEALTH RELEVANCE (provided by applicant): Urinary tract infection is the second most common type of infection In humans and accounts for $1.6 billion in US annual health care costs with almost $90 million in prescription antibiotics alone. The goal of this project is for the National Swine Resource and Research Center (NSRRC) and the Mutant Mouse Regional Resource Center (MMRRC) at the University of Missouri to work with the Duke University CTSA to utilize existing mouse and pja animal models for discoverv of drugs to treat Urinary tract infection.